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- W4361944187 abstract "<div>Abstract<p><b>Purpose:</b> Resistance to glucocorticoid (GC) is a significant problem in the clinical management of lymphoid malignancies. Addressing this issue via a mechanistic understanding of relevant signaling pathways is more likely to yield positive outcomes.</p><p><b>Experimental Design:</b> We used gene set enrichment analysis (GSEA), multiple genetic models of gain and loss of function in B-cell lymphoma cell lines, <i>in vitro</i> and <i>in vivo</i>, and primary patient samples to characterize a novel relationship between the cyclic AMP/phosphodiesterase 4B (cAMP/PDE4B), AKT/mTOR activities, and GC responses.</p><p><b>Results:</b> Starting from the GSEA, we found that overexpression of the <i>PDE4B</i> in diffuse large B-cell lymphoma (DLBCL) impinge on the same genes/pathways that are abnormally active in GC-resistant tumors. We used genetically modified cell lines to show that PDE4B modulates cAMP inhibitory activities toward the AKT/mTOR pathway and defines GC resistance in DLBCL. In agreement with these data, pharmacologic inhibition of PDE4 in a xenograft model of human lymphoma unleashed cAMP effects, inhibited AKT, and restored GC sensitivity. Finally, we used primary DLBCL samples to confirm the clinical relevance and biomarker potential of AKT/mTOR regulation by PDE4B.</p><p><b>Conclusions:</b> Together, these data mechanistically elucidated how cAMP modulates GC responses in lymphocytes, defined AKT as the principal transducer of the growth inhibitory effects of cAMP in B cells, and allowed the formulation of genomics-guided clinical trials that test the ability of PDE4 inhibitors to restore GC sensitivity and improve the outcome of patients with B-cell malignancies. <i>Clin Cancer Res; 17(21); 6723–32. ©2011 AACR</i>.</p></div>" @default.
- W4361944187 created "2023-04-05" @default.
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- W4361944187 date "2023-03-31" @default.
- W4361944187 modified "2023-10-14" @default.
- W4361944187 title "Data from Gene Set Enrichment Analysis Unveils the Mechanism for the Phosphodiesterase 4B Control of Glucocorticoid Response in B-cell Lymphoma" @default.
- W4361944187 doi "https://doi.org/10.1158/1078-0432.c.6520094" @default.
- W4361944187 hasPublicationYear "2023" @default.
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